2-Amino-1-arylethanol derivatives, such as albuterol (I) , terbutaline (II) , isoproterenol (III), and sotalol (IV), are well known pharmaceutical agents. ##STR1## These and other .beta.-adrenergic agents (.beta.-blockers or .beta.-agonists) are used in the treatment of asthma, glaucoma and cardiovascular diseases. As a class, the 2-amino-1-arylethanols possess at least one enantiogenic center. It is often the case that two enantiomers of a chiral drug display different biological activities, and although the enantiomers of many arylethanolamine drugs appear to exhibit this dichotomous activity, to date only a few optically pure arylethanolamine drugs have been prepared. This is probably because the synthetic approaches to arylethanolamines generally involve (1) tedious diastereomeric resolutions, (2) high-cost reagents, or (3) lengthy multistep syntheses with low overall yields. In fact, the only published method for preparation of an optically pure albuterol enantiomer is by the resolution of a benzyl-protected ester precursor [Hartley and Middlemiss, J. Med. Chem. 14, 895 (1971)]. A simple synthesis of enantiomerically pure arylethanolamines would be highly desirable.
Initially one might consider the enantiospecific reduction of the ketone functionality in an .alpha.-aminoketone, because .alpha.-aminoketones are common intermediates in the syntheses of the above-mentioned .beta.-agonists and .beta.-blockers. ##STR2## It has been reported that asymmetric hydrogenation of .alpha.-amino ketones in the presence of a ruthenium complex gives .alpha.-aminoalcohols with high enantioselectivity. However, catalytic hydrogenation is often less attractive than hydride-type reductions in that, with hydrides or borane, additional functionalities (such as the ester in an albuterol precursor) can, in principle, be reduced in the same step as the ketone.
Asymmetric reductions of prochiral ketones with borane in the presence of chiral oxazaborolidine catalysts are known, and high enantioselectivities have been observed with many ketones. Unfortunately, the high enantioselectivity observed with simple ketones has not been achieved in asymmetric borane reduction of .alpha.-amino substituted ketones, which give products characterized by disappointingly low enantiomeric excesses (ee).
.alpha.-Iminoketones are one step closer to starting material, and the simultaneous reduction of both the ketone and the imine functionalities would eliminate one step in the overall synthesis. ##STR3## The known racemic mixture of albuterol isomers(I) has, in at least one instance, been prepared by the chirally uncontrolled reduction of an .alpha.-iminoketone intermediate (PCT WO 92/04314). There are a few reports on the asymmetric reduction of the C.dbd.N functionality with borane, and in the few that have been reported, moderate asymmetric induction has been obtained in some cases [See Cho et al. J.Chem. Soc. Perkin Trans. I, 1990, 3200; and Cho et al. Tetrahedron: Asymmetry, 3, 337 (1992).] However, no methods appear to have been reported for the asymmetric reduction of .alpha.-iminoketones to give .alpha.-aminoalcohols.